In heart transplant patients and other transplant recipients, conventional imnnunosuppression is associated with a high incidence of unwanted long-term side effects, including renal insufficiency, infection, and malignancy. In addition, current approaches incompletely protect the graft from chronic rejection, which for the heart is manifest as "cardiac allograft vasculopathy" (CAV). The sponsor has developed a clinically relevant cynomolgus monkey heterotopic heart transplant model to study new treatment approaches to try to prevent this problem. The scientific goal of this research training fellowship is to apply new molecular diagnostic techniques (laser capture microdissection, or "LCM", of biopsies from the transplanted heart, followed by reverse transcription/polymerase chain reaction, or "RT/PCR", to quantify expression of particular genes in the heart) to improve our understanding of what causes CAV. Specifically, we will study how blocking a single molecule in the immune system, CD28, affects the expression of immune genes and scar tissue (fibrosis) genes in the blood vessels and adjacent heart tissue of monkey heart transplants. Heart biopsies will be obtained serially over time in individual heart transplant recipients, and compared between animals receiving anti-CD28 therapy relative to other treatments. We hypothesize that the balance of 1) immunomodulatory cytokine genes (Th1, Th2) and 2) fibrotic pathway genes (MMPs, FGFs, SM a-actin) associated with CAV are differentially modulated by selective CD28 costimulation pathway blockade relative to other approaches we have tried previously. This fellowship will fulfill the applicant's broad and long-term goal: to develop the intellectual and practical skills necessary to undertake independent translational research as the foundation for his future career in academic surgery, most likely in thoracic transplantation. With respect to public health, cardiovascular disease is a major cause of morbidity and mortality, and heart transplantation is the best available treatment for the subset of these patients lucky enough to receive a new heart. Unfortunately, over time, many transplanted hearts fail due to cardiac allograft vasculopathy, a condition we believe is a form of chronic rejection. Having a better understanding of the genes expressed in this process provides opportunity for targeting future therapies (immune modulators or antifibrotic agents) that may one day prevent cardiac allograft vasculopathy and improve long-term outcomes after heart transplantation. [unreadable] [unreadable] [unreadable]